Pharmaceutical stability aspects of nanomedicines - Future Medicine

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Nanomedicine (2009) 4(8), 857–860. EDITORIAL. “In all research and invesfigafion of nanomedicines, a more intensive effort is needed to prove their efficacy ...
Editorial

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Pharmaceutical stability aspects of nanomedicines “In all research and investigation of nanomedicines, a more intensive effort is needed to prove their efficacy and safety. Acceptable stability, along with efficacy and safety, is one of the important challenges in the area.” Pharmaceutical stability testing is a major investigation studying the changes in the quality of any drug product with respect to time under the influence of environmental factors, such as temperature, humidity and light. Stability testing is generally recommended during the product development of new drugs in order to establish a shelf-life for the drug product and to recommend a suitable storage condition. For all new drug products, including nanomedicines, stability testing should include the testing of all parameters that are susceptible to change during transportation and storage and are likely to influence the safety, efficacy and quality of these products [1,2] . The International Conference on Harm­ onisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) is a unique project that brings together the regulatory authorities of Europe, Japan and the USA, and experts from the pharmaceutical industry in these three regions to discuss scientific and technical aspects of drug-product registration [101] . In the pharmaceutical industry, stability studies for new drug products are commonly performed following the ICH guidelines. The procedures for stability testing of new drug products, new dosage forms and on biotechnological-based drug products are available in the ICH guidelines Q1A (R2), Q1C and Q5C, respectively. Nanomedicines, which are medical applications of nanotechnology, are promising candidates for drug delivery and imaging. In addition, attempts were made to introduce a comprehensive definition for nanoparticles in nanomedicines. For pharmaceutical purposes: “Nanoparticles are solid colloidal particles ranging in size from 10 to 1000 nm (1 µm), they consist of macromolecular materials in which the active principle (drug or biologically active material) is dissolved, entrapped, encapsulated and/or to which the active principle is adsorbed or attached” [3] .

Recently, various targeted/nontargeted nanomedicines (e.g., polymeric nanoparticles, solid lipid nanoparticles, micelles, dendrimers, liposomes, gold nanoparticles, fluorescent nanoparticles, polymer conjugates and magnetic nanoparticles) and multifunctional nanomedicines (e.g., nanomicelles, dendrimers and magnetic nanoparticles) have been reported for drug delivery and imaging [4–11] . Nontargeted nanomedicines are free from the regulations for biotechnological products, which can follow the regulations for the procedures of ICH guidelines Q1A (R2) and Q1C. The targeted nanomedicines, however, are mostly incorporated with biotechnological products (e.g., cancer-targeting antibodies or peptides). Therefore, stability testing of these types of drug products can consider/follow the procedures of ICH guideline Q5C [12] . A review of the literature indicates that although limited attention has been given to the thermal stability testing of these targeted/non­ targeted nanomedicines developed for drug delivery and imaging, the stability aspects of some nanomedicines, such as polymeric nanoparticles, solid lipid nanoparticles and liposomes, have been well studied [13–15] . This article will therefore focus on the importance of pharmaceutical stability aspects and its future impact on the quality of nanomedicines.

10.2217/NMM.09.75 © 2009 Future Medicine Ltd

Nanomedicine (2009) 4(8), 857–860

Madaswamy S Muthu Author for correspondence: Department of Pharmacology, Institute of Medical Sciences, Banaras Hindu University, Varanasi – 221005, India Tel.: +91 923 519 5928; Fax: +91 542 236 7568; [email protected]

Si-Shen Feng Department of Chemical & Biomolecular Engineering, National University of Singapore, Block E4, 05-12, Engineering Drive 3, 117576, Singapore

Pharmaceutical stability testing All nanomedicines should be evaluated under transportation and storage conditions (long term and accelerated) for their thermal stability and sensitivity to moisture. Accelerated thermal stability testing involves the use of higher temperatures for quick reactions that can be extrapolated to a desired storage condition. In general, longterm and accelerated storage conditions recommended by ICH guidelines are 25°C ± 2°C/60% relative humidity (RH)  ±  5%RH and 40°C ± 2°C/75%RH ± 5%RH, respectively. If ISSN 1743-5889

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appropriate, an intermediate storage condition (30°C ± 2°C/65%RH ± 5%RH) is recommended, as per the ICH guidelines [1] . Furthermore, photostability testing is recommended for drug products containing light-sensitive drugs, as per ICH guideline Q1B [16] . In addition, if any drug products are intended for storage in a refrigerator, long-term and accelerated storage conditions recommended by the ICH guidelines are 5°C ± 3°C and 25°C ± 2°C/60%RH ±5%RH, respectively. If any drug products are intended for storage in a freezer, only the long-term storage condition of ‑20°C ± 5°C is recommended  [1] . As new drug products, nanomedicines should demonstrate physical, chemical and microbiological parameters under suitable thermal storage conditions and durations as per ICH guidelines before ­product registration.

„„ Stability testing of nanomedicines free from biotechnological products Nontargeted nanomedicines are generally designed without the incorporation of biotechno­ logical products. These nanomedicines are loaded only with a drug and/or imaging agent. Stability testing of these drug products follow the procedures of the ICH guidelines Q1A (R2) and Q1C (for new dosage forms).

“Stability problems are major issues in drug products/nanomedicines incorporated with biotechnological products … Most nanomedicines incorporated with biotechnological products need precisely defined storage conditions…”

Lemoine and colleagues evaluated the stability of nanoparticles prepared with poly(e‑caprolactone), poly(d,l-lactide) and poly(d,l-lactide-coglycolide) polymers, which are stored at different temperatures, such as 16, 4 and 37°C (room temperature) [17] . The authors finally recommended suitable storage conditions of 4  and 37°C for these polymeric nano­particles. Nanoparticles based on copolymers, such as poly(d,l-lactide-coglycolide)-monomethoxy poly(ethyleneglycol) also proved their stability at 4 and 37°C [18] . In one study, lyophilized preparations of solid lipid nanoparticles were stored under three different sets of temperatures and humidities as per ICH guidelines: 25°C/60%RH, 30°C/65%RH and 40°C/75%RH. Results showed that solid lipid nanoparticles maintained or increased stability during storage at 25°C/60%RH and 30°C/65%RH, but were unstable if they were stored at 40°C/75%RH [14] . 858

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In another study by Mulik and colleagues [19] , prepared curcuminoid (a light-sensitive drug)loaded poly(butyl cyanoacrylate) nanoparticles and stored them at 40°C/75%RH in the presence and absence of light for 6 months for stability testing. No changes were observed with regard to the stability of nanoparticles (except drug content) stored at 40°C/75%RH in the presence and absence of light for 6 months. The percentage drug content in curcuminoid-loaded poly(butyl cyanoacrylate) nanoparticles after 6 months kept at 40°C/75%RH in the absence of light was found to be inbetween 87 and 93%, and was reduced to between 79 and 89% in the presence of sunlight, showing the effect of light on the stability of curcuminoids. In the literature, the thermal stability of most liposomes at 4°C and 25°C have been proven, as per the ICH guidelines, by various researchers [20,21] . Results are available for the thermal stability studies of polymeric nanoparticles, solid lipid nanoparticles and liposomes. Furthermore, some information is available on the other ­stability aspects of micelles [22] , dendrimers [23] , ­magnetic nanoparticles [24] and polymer conjugates [25] . Nevertheless, there is little ­information available in the literature on the thermal ­stability of micelles, dendrimers and magnetic nanoparticles.

„„ Stability testing of nanomedicines incorporated with biotechnological products Targeted nanomedicines are generally designed by incorporating biotechnological products (e.g., cancer-targeting antibodies and cancertargeting peptides) [4] . Some types of nano­ medicines are loaded with proteins, genes and insulin, for example. These drug products can consider the procedures of ICH guideline Q5C for stability testing. Stability problems are major issues in drug products/nanomedicines incorporated with biotechnological products [26] . Most nano­medicines incorporated with biotechnological products need precisely defined storage conditions, which mainly depend upon the biotechnological ­product (owing to their stability problems) [12] . Only a few reports are available on the thermal stability testing of targeted nanomedicines or nanomedicines incorporated with biological products. For example, Karau and colleagues investigated the stability of human IFN‑a-loaded nanosized liposomes at 8, 20 and 37°C  [27] . The results demonstrated the pharmaceutical requirements for liposomes of uniform size distribution and stability were stored future science group

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at 8°C for 3 months. However, loss of stability was reported from the initial total activity of human IFN‑a at 20°C and 37°C.

characterization  [12] . These parameters should be included in the stability protocol to achieve maximum safety and quality.

Physical, chemical & microbiological parameters commonly used to study the stability of different nanomedicines All types of nanomedicines (targeted/non­ targeted) are commonly analyzed during stability testing for physical, chemical and microbiological parameters, such as physical appearance and morpho­logy, particle size and size distribution, surface charge and surface chemistry, drug content and pH value, drug loading and release kinetics and in vitro degradation and dissolution [8,9,17] . In some cases, drug leakage studies are reported in stability testing (i.e., liposomes) [21] . Most of the thermal stability procedures were investigated at approximately 4°C and 37°C. The duration of storage was not strictly followed in these studies, but is expected to be up to 12 months (long-term storage), as per ICH guidelines. For nanomedicines incorporated with biotechnological products (e.g., cancer-targeting ligandconjugated nanomedicines), additional stability parameters are suggested in the ICH guideline Q5C. The additional parameters applicable, as per ICH guideline Q5C, are potency of the biotechnological product, dissociation of active moieties from nanomedicines, purity and molecular

Concluding remarks Nanomedicines in this editorial are defined as drugs formulated in nanocarriers (sometimes incorporated with biotechnological ­products), which are innovative drug products of a ­multidisciplinary approach. Nanomedicines will not be successful pharmaceutical drug products until they are investigated for various quality aspects, such as pharmaceutical stability testing. In all research and investigation of nanomedicines, a more intensive effort is required to prove their efficacy and safety. Acceptable stability, along with efficacy and safety, is one of the important challenges in the area. Consideration of how to apply the ICH guidelines strictly for stability testing will improve the quality of the emerging nanomedicines.

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Financial & competing interests disclosure The authors have no relevant affiliations or financial ­involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes ­employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or ­pending, or royalties. No writing assistance was utilized in the production of this manuscript.

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